The human cell surface glycoprotein CD4 is the cellular receptor for the HIV (HIV) and binds with high affinity to the HIV exterior envelope glycoprotein, gpl20. At present, a detailed molecular picture of this interaction is unavailable because of the overall complexity of these molecules and the difficulty in obtaining large quantities of purified, native, recombinant HIV gpl20 due to inherent difficulties in achieving high-level expression in mammalian cells. The goal of this Phase I proposal is to generate eukaryotic expression vectors encoding HIV-l gpl20 that will direct the high-level expression in mammalian cells of gpl20 in a system amenable to large-scale production. The major advantage of the system they propose to develop over already existing systems is that expression will be stable, virus-free, and will encode native, correctly glycosylated HIV-l gpl20. The goal of developing this expression system is to produce large quantities of material for detailed biochemical, biophysical, crystallographic, and immunologic investigations. These studies will not only provide a precise molecular description of the binding of HIV gpl20 to CD4, but will also provide new insight into the interactions between HIV and the host immune system. A detailed understanding of these events will permit the design both of novel therapeutic agents which inhibit this step in the viral replicative-cycle and of recombinant vaccines.